Boron tribromide → 3-(4-{[4-[5-Fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)phenol

HRID 418806Notes

Reaction equation

HRID 418806 reaction equation
[F:1][C:2]([F:39])([F:38])[C:3]([CH2:18][NH:19][C:20]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][N:24]2[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36]C)[CH:31]=1)([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].C(=O)=O.CC(C)=O.B(Br)(Br)Br>ClCCl>[F:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4][C:3]([OH:17])([C:2]([F:1])([F:39])[F:38])[CH2:18][NH:19][C:20]2[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]3[C:21]=2[CH:22]=[N:23][N:24]3[C:30]2[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=2)[CH:13]=1

Participants

5

Reactant 3

HCID 25134Boron tribromide3×HCID 18522661Acetone cardiceHCID 576159421,1,1-Trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-[({6-methyl-1-[3-(methyloxy)phenyl]-1H-indazol-4-yl}amino)methyl]-2-pentanol

Product 1

HCID 576159303-(4-{[4-[5-Fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)phenolYield 19.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

1,1,1-Trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-[({6-methyl-1-[3-(methyloxy)phenyl]-1H-indazol-4-yl}amino)methyl]-2-pentanol (Example 22, 46 mg, 0.085 mmol) was dissolved in anhydrous dichloromethane (4 ml) and cooled to −70° C. (cardice/acetone bath). Boron tribromide (1.0M in dichloromethane, 0.15 ml, 0.15 mmol) was added and the mixture allowed to warm to room temperature over 2 hours and then stirred for a further 20 hours. The mixture was cooled to −70° C. and more boron tribromide (1.0M in dichloromethane, 0.1 ml, 0.1 mmol) was added and the mixture was allowed to warm to room temperature and stirred for a further 20 hours. The mixture was cooled again to −70° C. and more boron tribromide (1.0M in dichloromethane, 0.1 ml, 0.1 mmol) was added and the mixture was allowed to warm to room temperature and stirred for a further 32 hours. The mixture was then diluted with dichloromethane (15 mL), cooled in ice and quenched with methanol (3 mL). After a further 15 min the mixture was partitioned between dichloromethane (35 mL) and aqueous sodium bicarbonate (35 mL). The organic phase was washed again with aqueous sodium bicarbonate (35 mL), passed through a hydrophobic frit and evaporated under reduced pressure to yield crude material. This crude product was purified by mass-directed autopreparation to give the title compound (9 mg).

Workup

  1. temperatureThe mixture was cooled to −70° C.
  2. temperatureto warm to room temperature
  3. stirringstirred for a further 20 hours
  4. temperatureThe mixture was cooled again to −70° C.
  5. temperatureto warm to room temperature
  6. stirringstirred for a further 32 hours
  7. temperaturecooled in ice
  8. customquenched with methanol (3 mL)
  9. customAfter a further 15 min the mixture was partitioned between dichloromethane (35 mL) and aqueous sodium bicarbonate (35 mL)
  10. washThe organic phase was washed again with aqueous sodium bicarbonate (35 mL)
  11. customevaporated under reduced pressure
  12. customto yield crude material
  13. customThis crude product was purified by mass-directed autopreparation

Sources & evidence

ORD record
ord-d02ac2107a7f417c862a9b0f12b33e35
Source dataset
uspto-grants-2012_01
Patent number
US08093281B2

Reaction notes

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